EP2385769A1 - Schnell lösliche vitaminformulierung und verfahren zu ihrer anwendung - Google Patents

Schnell lösliche vitaminformulierung und verfahren zu ihrer anwendung

Info

Publication number
EP2385769A1
EP2385769A1 EP09836849A EP09836849A EP2385769A1 EP 2385769 A1 EP2385769 A1 EP 2385769A1 EP 09836849 A EP09836849 A EP 09836849A EP 09836849 A EP09836849 A EP 09836849A EP 2385769 A1 EP2385769 A1 EP 2385769A1
Authority
EP
European Patent Office
Prior art keywords
tablet
per tablet
per
set forth
active ingredient
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP09836849A
Other languages
English (en)
French (fr)
Other versions
EP2385769A4 (de
Inventor
Angela Sutterer
Suzanne M. Yachechak
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Valeant Pharmaceuticals Luxembourg SARL
Original Assignee
Fleming and Company Pharmaceuticals
Fleming and Co Pharmaceuticals
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Fleming and Company Pharmaceuticals, Fleming and Co Pharmaceuticals filed Critical Fleming and Company Pharmaceuticals
Publication of EP2385769A1 publication Critical patent/EP2385769A1/de
Publication of EP2385769A4 publication Critical patent/EP2385769A4/de
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7135—Compounds containing heavy metals
    • A61K31/714—Cobalamins, e.g. cyanocobalamin, i.e. vitamin B12
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/15—Vitamins
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/16—Inorganic salts, minerals or trace elements
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/40—Complete food formulations for specific consumer groups or specific purposes, e.g. infant formula
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/07—Retinol compounds, e.g. vitamin A
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid, pantothenic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/28—Compounds containing heavy metals
    • A61K31/315—Zinc compounds
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • A61K31/355—Tocopherols, e.g. vitamin E
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
    • A—HUMAN NECESSITIES
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4415—Pyridoxine, i.e. Vitamin B6
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A61K31/51—Thiamines, e.g. vitamin B1
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/525—Isoalloxazines, e.g. riboflavins, vitamin B2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
    • A61K31/593—9,10-Secocholestane derivatives, e.g. cholecalciferol, i.e. vitamin D3
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/02—Nutrients, e.g. vitamins, minerals
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs

Definitions

  • the present invention generally relates to rapidly dissolvable nutritional compositions and methods of providing nutritional supplementation to candidates for, patients undergoing, or patients having undergone bariathc surgery, to patients suffering renal disease, and to candidates for or patients undergoing dialysis.
  • B vitamins such as Bi, B 2 , B 3 , B 5 , B 6 , B 7 , Bi 2 , and folic acid
  • vitamin C fat soluble vitamins
  • essential minerals such as iron, selenium, copper, manganese, molybdenum, calcium, magnesium, and zinc
  • a rapidly dissolvable nutritional supplement composition has been developed as a quick dissolve tablet with a smooth mouth feel that disintegrates in less than about 90 seconds without the need for contemporaneous administration of exogenous liquids.
  • the vitamin taste, as well as the mineral taste if minerals are present is masked with flavor and sweetener.
  • the nutritional composition of the present invention avoids or alleviates problems associated with conventional nutritional supplement pills or tablets and, therefore, results in improved patient compliance with and effectiveness of a post-operative nutritional supplement regimen or a renal or dialysis regimen.
  • a rapidly dissolvable tablet for oral administration to a patient having undergone bariathc surgery and a method for providing nutritional supplementation to a bariathc patient utilizing such a tablet.
  • one aspect of the present invention is directed to a method for providing nutritional supplementation to a patient having undergone bahatric surgery.
  • the method comprises orally administering to the patient a rapidly dissolving tablet, the tablet comprising; an active ingredient component comprising one or more vitamins or minerals; a disintegrant; and a directly-compressible, water- soluble carbohydrate; wherein the tablet dissolves in the mouth of the patient within about 90 seconds after administration of the tablet.
  • the active ingredient component comprises a mixture of two or more B vitamins selected from the group consisting of B 1 , B 2 , B 3 , B 5 , B 6 , B 7 , B 9 , and B 12 ; one or more non-B vitamins; and one or more minerals.
  • Another aspect of the present invention is a method for providing nutritional supplementation to a patient having undergone bahatric surgery.
  • the method comprises orally administering to the patient a rapidly dissolving tablet, the tablet comprising an active ingredient component comprising a mixture of two or more B vitamins selected from the group consisting of B 1 , B 2 , B 3 , B 5 , B 6 , B 7 , B 9 , and B 12 ; one or more non-B vitamins; and one or more minerals, the active ingredient component being substantially free of therapeutic quantities of calcium and/or magnesium; a disintegrant; and a directly-compressible, water-soluble carbohydrate; wherein the tablet dissolves in the mouth of the patient within about 90 seconds after administration of the tablet; orally administering to the patient a second tablet, the tablet comprising therapeutic quantities of calcium and/or magnesium.
  • Another aspect of the present invention is a method for providing nutritional supplementation to a candidate for bariathc surgery.
  • the method comprises orally administering to the candidate a rapidly dissolving tablet, the tablet comprising an active ingredient component comprising one or more vitamins or minerals; a disintegrant; and a directly-compressible, water-soluble carbohydrate; wherein the tablet dissolves in the mouth of the patient within about 90 seconds after administration of the tablet.
  • the active ingredient component comprises a mixture of two or more B vitamins selected from the group consisting of B 1 , B 2 , B 3 , B 5 , B 6 , B 7 , B 9 , and B 12 ; one or more non-B vitamins; and one or more minerals.
  • Another aspect of the present invention is a rapidly dissolving tablet for oral administration for use in providing nutritional supplementation to a patient having undergone bahatric surgery.
  • the tablet comprises an active ingredient component comprising a mixture of two or more B vitamins selected from the group consisting of B 1 , B 2 , B 3 , B 5 , B 6 , B 7 , B 9 , and B 12 ; one or more non-B vitamins; and one or more minerals; a disintegrant; and a directly-compressible, water-soluble carbohydrate; wherein the tablet dissolves in the mouth of the patient within about 90 seconds after administration of the tablet.
  • B vitamins selected from the group consisting of B 1 , B 2 , B 3 , B 5 , B 6 , B 7 , B 9 , and B 12 ; one or more non-B vitamins; and one or more minerals; a disintegrant; and a directly-compressible, water-soluble carbohydrate; wherein the tablet dissolves in the mouth of the patient within about 90 seconds after administration of
  • Another aspect of the present invention is a rapidly dissolving tablet for oral administration for use in providing nutritional supplementation to a patient having undergone bahatric surgery.
  • the tablet comprises an active ingredient component comprising a mixture of two or more B vitamins selected from the group consisting of Bi, B 2 , B 3 , B 5 , B 6 , B 7 , B 9 , and Bi 2 ; one or more non-B vitamins; and one or more minerals, the active ingredient component being substantially free of therapeutic quantities of calcium and/or magnesium; a super disintegrant; and a directly-compressible, water-soluble mannitol; wherein the tablet is sugar free.
  • a rapidly dissolvable tablet for oral administration to a renal patient or a patient undergoing dialysis and a method for providing nutritional supplementation to a renal or dialysis patient utilizing such a tablet.
  • one aspect of the present invention is directed to a method for providing nutritional supplementation to a renal or dialysis patient.
  • the method comprises orally administering to the patient a rapidly dissolving tablet, the tablet comprising an active ingredient component comprising one or more vitamins; a disintegrant; and a directly-compressible, water-soluble carbohydrate; wherein the tablet dissolves in the mouth of the patient within about 90 seconds after administration of the tablet.
  • the active ingredient component comprises a mixture of two or more B vitamins selected from the group consisting of Bi, B 2 , B 3 , B 5 , B 6 , B 7 , B 9 , and Bi 2 ; and one ore more non-B vitamins.
  • the one or more non-B vitamins is vitamin C.
  • Another aspect of the present invention is a method for providing nutritional supplementation to a renal or dialysis patient.
  • the method comprises orally administering to the patient a rapidly dissolving tablet, the tablet comprising an active ingredient component comprising a mixture of two or more B vitamins selected from the group consisting of Bi, B 2 , B 3 , B 5 , B 6 , B 7 , B 9 , and Bi 2 , and one or more non- B vitamins, the active ingredient component being substantially free of phosphorous, potassium, and/or sodium; a disintegrant; and a directly-compressible, water-soluble carbohydrate; wherein the tablet dissolves in the mouth of the patient within about 90 seconds after administration of the tablet.
  • the one or more non-B vitamins is vitamin C.
  • Another aspect of the present invention is a method for providing nutritional supplementation to a candidate for dialysis.
  • the method comprises orally administering to the candidate a rapidly dissolving tablet, the tablet comprising an active ingredient component comprising one or more vitamins; a disintegrant; and a directly-compressible, water-soluble carbohydrate; wherein the tablet dissolves in the mouth of the patient within about 90 seconds after administration of the tablet.
  • the active ingredient component comprises a mixture of two or more B vitamins selected from the group consisting of Bi, B 2 , B 3 , B 5 , B 6 , B 7 , B 9 , and Bi 2 ; and one or more non-B vitamins.
  • the one or more non-B vitamins is vitamin C.
  • Another aspect of the present invention is a rapidly dissolving tablet for oral administration for use in providing nutritional supplementation to a renal or dialysis patient.
  • the tablet comprises an active ingredient component comprising a mixture of two or more B vitamins selected from the group consisting of Bi, B 2 , B 3 , B 5 , B 6 , B 7 , B 9 , and B 12 , and one or more non-B vitamins; a disintegrant; and a directly-compressible, water-soluble carbohydrate; wherein the tablet dissolves in the mouth of the patient within about 90 seconds after administration of the tablet.
  • the one or more non-B vitamins is vitamin C.
  • Another aspect of the present invention is a rapidly dissolving tablet for oral administration for use in providing nutritional supplementation to a renal or dialysis patient.
  • the tablet comprises an active ingredient component comprising a mixture of two or more B vitamins selected from the group consisting of Bi, B 2 , B 3 , B 5 , B 6 , B 7 , B 9 , and B 12 , and one or more non-B vitamins, the active ingredient component being substantially free of phosphorous, potassium, and/or sodium; a super disintegrant; and a directly-compressible, water-soluble carbohydrate; wherein the tablet is sugar free.
  • the one or more non-B vitamins is vitamin C.
  • FIGURE 1 is a schematic flow diagram illustrating a process for the preparation of the rapidly dissolving nutritional supplement tablet described herein.
  • FIGURE 2 graphically depicts the results of the tablet hardness test in Examples 1 and 2.
  • FIGURE 3 graphically depicts the results of the oral disintegration test in Examples 1 and 2.
  • FIGURE 4 graphically depicts the results of the friability test in Examples 1 and 2.
  • FIGURE 5 graphically depicts the results of the shipping test in Examples 1 and 2.
  • FIGURE 6 graphically depicts the results of the tablet hardness over time test in Example 3.
  • FIGURE 7 graphically depicts the results of the simulated patient test in Example 3.
  • FIGURE 8 graphically depicts the hardness of tablets produced during a production run according to Example 3.
  • FIGURE 9 graphically depicts the weight of tablets produced during a production run according to Example 3.
  • FIGURE 10 graphically depicts the thickness of tablets produced during a production run according to Example 3.
  • the present invention is based in part on the observation that administration of nutritional supplements to bariatric patients (sometimes referred to herein as "patients having undergone bariatric surgery” or “bariatric surgery patients”) poses unique problems in the first several months following bariatric surgery.
  • dietary restrictions and malabsorption issues caused in large part by the substantial decrease in the size of the digestive anatomy, create unique issues related to nutritional supplementation for bariatric surgery patients.
  • patient compliance with prior known nutritional supplementation regimens is also undermined, resulting in the potential for inconsistent and ineffective nutritional supplementation.
  • the present invention is also based in part on the observation that administration of nutritional supplements to renal patients and dialysis patients (sometimes referred to herein as "patients undergoing dialysis” or “hemodialysis patients”) pose similar problems.
  • patients undergoing dialysis patients sometimes referred to herein as "patients undergoing dialysis” or "hemodialysis patients”
  • dietary modifications or restrictions, vitamin malabsorption issues due to administration of other medications, and loss of vitamins to dialysis treatments create unique issues related to nutritional supplementation for renal and dialysis patients.
  • patient compliance with prior known nutritional supplementation regimens is also undermined, resulting in the potential for inconsistent and ineffective nutritional supplementation.
  • the present invention is directed to methods for providing nutritional supplementation and maintaining necessary vitamin serum levels in these patients by orally administering to the patient a rapidly dissolvable tablet, preferably in the absence of concurrent oral administration of a liquid to the patient.
  • the nutritional supplement tablet comprises an active ingredient component comprising, in one embodiment, a mixture of two or more B vitamins, and one or more non-B vitamins.
  • the active ingredient component also comprises one or more minerals.
  • the tablet also comprises a disintegrant or a super disintegrant, and a directly compressible, water-soluble carbohydrate.
  • directly compressible carbohydrates are well known in the art, and have flow and compression characteristics that make them compatible for use in high speed tableting processes without further augmentation or adjustments to the carbohydrates or the tableting processes (e.g., without the addition of a glidant, such as, for example, silicon dioxide) to increase flowability of the carbohydrate.
  • a glidant such as, for example, silicon dioxide
  • Such carbohydrates will be free flowing, allowing for rapid and homogenous flow of the carbohydrate during die filling and preventing common problems attributed to improper powder flow, such as non-uniformity in blending, under/over dosage of active ingredients, and inaccurate (e.g., incomplete or over) die filling.
  • such a directly compressible carbohydrate will also have excellent compressibility with minimal to nonexistent elastic recovery, causing the tableted mass to remain in its compressed form once pressure is removed.
  • the tablet will also contain a flavor component and a sweetener component in order to mask any unpleasant flavors associated with the active ingredient component, as well as other excipients used to provide the tablet with acceptable organoleptic properties (e.g., a pleasant mouth feel, tablet texture, tablet taste, etc.).
  • oral administration of the tablet will result in the tablet dissolving upon contacting saliva in the mouth of the patient within about 90 seconds or less, thereby making the active ingredients in the tablet available for absorption in the digestive system of the patient almost immediately.
  • the present nutritional composition and methods of nutritional supplementation were developed and are particularly suitable for patients having a limited digestive anatomy, such as for example those having recently undergone bahatric surgery (e.g., gastric banding or gastric bypass surgery), as well as for those on restrictive diet or fluid regimens, such as, for example, renal or dialysis patients.
  • bahatric surgery e.g., gastric banding or gastric bypass surgery
  • restrictive diet or fluid regimens such as, for example, renal or dialysis patients.
  • bariatric patients are at an increased risk of nutritional deficiencies due to the changes in digestive anatomy (i.e., changes to the size of or constrictions in the stomach and intestines) and the increased occurrence of persistent patient vomiting. Not only do these factors cause an increase in risk of nutritional deficiencies, but they also make conventional forms of nutritional supplementation inefficient and sometimes simply physically or feasibly impossible to utilize.
  • B vitamins such as Bi, B 2 , B 3 , B 5 , B 6 , B 7 , Bi 2 , and folic acid
  • vitamin C fat soluble vitamins
  • essential minerals such as iron, selenium, copper, calcium, magnesium, manganese, molybdenum, and zinc
  • renal and dialysis patients often encounter vitamin, and in particular vitamin B and vitamin C, deficiencies.
  • dialysis often removes water soluble vitamins, and in particular the B vitamins and vitamin C, from the blood of the dialysis patients, thereby requiring constant vitamin replenishment or supplementation. This supplementation is further complicated by the fact that many renal and all and dialysis patients are also greatly limited in the amount of fluids they can consume on a daily basis.
  • the present methods and nutritional supplement compositions are particularly suitable for bahatric, renal, and dialysis patients as an alternative to nutritional supplementation in which a conventional nutritional supplement composition is administered in the form of a hard pill or tablet not readily dissolvable in the mouth of a patient, and in particular, such a conventional pill or tablet that cannot be easily swallowed without the concurrent administration of or in conjunction with a liquid.
  • An example of such a patient is a person that has recently undergone some form of bahatric surgery, such as, for example, bypass surgery, such as gastric bypass surgery, wherein the stomach is reduced in size and food from the minimized stomach is forced to bypass part of the small intestine (an example of which is Roux-en-Y gastric bypass), gastric banding surgery, such as laparoscopic adjustable gastric banding or vertical banded gastroplasty, wherein an adjustable band is place around a portion of the stomach to restrict the efflux, and therefore, limit the influx, of food, or some combination of the two.
  • Another example of such a patient is a renal patient having compromised kidney function or complete kidney failure, and in particular, such a patient undergoing kidney dialysis. Because of the limit on absorption, intake, or both, the vitamin compositions and methods of administration utilizing the same are of benefit to such patients.
  • the treatment methods disclosed herein are applicable for nutritional supplementation and maintenance of vitamin blood serum levels in a patient following bariatric surgery, including but not limited to gastric bypass or gastric banding, to renal patients, and to patients undergoing dialysis, and in particular such patients in need of vitamin B supplementation and/or maintenance, and in particular, vitamin Bi 2 supplementation and/or maintenance.
  • Such a patient may be suffering from a vitamin Bi 2 deficiency, a disorder resulting from such a deficiency, or a disorder mimicking the symptomatology of such a deficiency due to, for example, malabsorption of vitamin Bi 2 as a result of the reduction in the digestive anatomy following bariatric surgery, e.g., reduced or insufficient secretion and/or utilization of intrinsic factor; dietary restrictions or changes as a result of compromised or failed kidney function, such as, for example, in a renal or dialysis patient; or recurring removal and loss of these vitamins from a renal patient's blood as a result of dialysis treatments.
  • disorders resulting from or mimicking a vitamin Bi 2 deficiency include, for example, anemia, including pernicious anemia; nerve and brain degeneration, typically as a result of degradation or lack of myelin; and impaired heart or cardiovascular function.
  • the present treatment methods are also applicable for nutritional supplementation and maintenance of vitamin blood serum levels in a patient that is to undergo bariatric surgery (i.e., pre-operative supplementation and maintenance).
  • certain of the vitamins contained in the nutritional supplement disclose herein, and in particular vitamin Bi are particularly beneficial for patients that are candidates for bariatric surgery.
  • such candidates typically are in need of Bi, as it is essential for metabolism via its coenzyme functions.
  • surgery candidates often have excess carbohydrate intake increasing the need for Bi .
  • Bi is not appreciably stored in the body, it may be depleted within two weeks or less on a Bi- free diet. Due to this, many bariatric surgical candidates may suffer from a Bi deficiency even before surgery.
  • the present nutritional supplement compositions are also particularly suitable for administration to patients that are candidates for bahatric surgery in accordance with the present methods providing for nutritional supplementation.
  • the nutritional compositions disclosed herein may be orally administered to patients that are candidates for bariathc surgery in accordance with the methods disclosed herein with respect to bariathc surgery patients.
  • the present treatment methods are also applicable for nutritional supplementation and maintenance of vitamin levels in a patient that is to undergo dialysis (i.e., pre-dialysis supplementation and maintenance).
  • the B-vitamins and vitamin C are removed from the blood during dialysis. Accordingly, proper loading of these vitamins in the body, and in particular the tissues, are particularly beneficial for these patients so that they have proper concentrations of the same ready for the body to use upon completion of the dialysis treatment.
  • the present nutritional supplement compositions are also particularly suitable for administration to patients that are candidates for dialysis in accordance with the present methods providing for nutritional supplementation.
  • the nutritional compositions disclosed herein may be orally administered to patients that are candidates for dialysis in accordance with the methods disclosed herein with respect to patients undergoing dialysis.
  • the present invention is directed particularly to the treatment of human patients having undergone bahatric surgery or that are renal or dialysis patients.
  • the methods disclosed herein are generally applicable to the treatment of mammals including, for example, domesticated house pets, such as dogs and cats, as well as farm animals, such as cattle, pigs, horses, sheep and goats, wherein it is typically difficult to administer an otherwise non-dissolving tablet to the mammal, as methods of masking the tablet by the concurrent administration of liquids or, in particular, additional foodstuffs, makes the typical administration of such tablets difficult and sometimes physically impossible.
  • the supplementation methods of the present invention comprise the oral administration of a rapidly dissolvable tablet as described in greater detail herein.
  • one embodiment of the invention comprises orally administering to the patient a rapidly dissolving tablet, the tablet, in one embodiment, comprising an active ingredient component comprising a mixture of two or more B vitamins selected from the group consisting of Bi, B 2 , B 3 , B 5 , B 6 , B 7 , B 9 , and Bi 2 ; one or more non-B vitamins; and one or more minerals; a disintegrant; and a directly- compressible, water-soluble carbohydrate; wherein the tablet dissolves in the mouth of the patient within about 90 seconds or less after administration of the tablet and otherwise exhibits acceptable organoleptic properties.
  • B vitamins selected from the group consisting of Bi, B 2 , B 3 , B 5 , B 6 , B 7 , B 9 , and Bi 2
  • one or more non-B vitamins selected from the group consisting of Bi, B 2 , B 3 , B 5 , B 6 , B 7 , B 9 , and Bi 2
  • one or more non-B vitamins selected from the group consisting of Bi
  • the tablet comprises an active ingredient component comprising a mixture of two or more B vitamins selected from the group consisting of B 1 , B 2 , B 3 , B 5 , B 6 , B 7 , B 9 , and Bi 2 ; one or more non-B vitamins; a disintegrant; and a directly-compressible, water- soluble carbohydrate; wherein the tablet dissolves in the mouth of the patient within about 90 seconds or less after administration of the tablet and otherwise exhibits acceptable organoleptic properties
  • the non-B vitamin is vitamin C.
  • administration of the nutritional composition does not include concurrent oral administration of a liquid to the patient.
  • the method of the present invention may include contemporaneous or concurrent administration of liquids to the patient in conjunction with administration of the nutritional supplement tablet.
  • Nutritional supplementation in accordance with the present invention comprises orally administering to the patient one or more rapidly dissolving tablets.
  • two such tablets each containing the mixture of two or more B vitamins, one or more non-B vitamins, and optionally one or more minerals as detailed below, are orally administered.
  • These tablets may be orally administered contemporaneously, such as for example, one or more tablets being administered simultaneously, or one or more tablets being administered within several minutes of one another (i.e., one tablet is administered, and, shortly after dissolving in the patient's mouth, a second tablet is orally administered).
  • two or more tablets could be administered over a period of time, such as for example one tablet being orally administered at a given time of day and a second tablet being orally administered at a later time of day, such as for example, twelve hours later.
  • the purpose remains to provide nutritional supplementation to the patient in the form of an orally administered, rapidly dissolvable tablet that does not require the concurrent administration of a liquid.
  • the above described method may also comprise the step of administering an additional vitamin tablet that may or may not be rapidly dissolvable and that may or may not contain the same active ingredients or components as the rapidly dissolving tablet.
  • the rapidly dissolvable tablet may not contain therapeutic concentrations of calcium and/or magnesium. Therefore, it may be necessary to orally administer those minerals as a separate tablet.
  • the present method for providing vitamin supplementation to a patient may also comprise the step of orally administering to the patient a second tablet, said tablet comprising an active ingredient component that is different from that contained in the rapidly dissolvable tablet.
  • the second tablet will be administered within about 4, preferably about 6, more preferably about 8, still more preferably about 10, and most preferably about 12 hours of administering the rapidly dissolvable tablet.
  • the second tablet is also a rapidly dissolving tablet, and more preferably a rapidly dissolving tablet comprising therapeutic concentrations of calcium and/or magnesium.
  • the calcium and magnesium is preferably present in the citrate forms (i.e., as calcium citrate and magnesium citrate).
  • the second tablet is a hard, non-rapidly dissolving tablet (i.e., a tablet that is typically administered concurrently with at least a small amount of liquid to facilitate easy swallowing of the tablet), and more preferably a hard, non-rapidly dissolving tablet comprising therapeutic concentrations of calcium and/or magnesium.
  • a hard, non-rapidly dissolving tablet i.e., a tablet that is typically administered concurrently with at least a small amount of liquid to facilitate easy swallowing of the tablet
  • a hard, non-rapidly dissolving tablet comprising therapeutic concentrations of calcium and/or magnesium.
  • the methods disclosed above may be used to administer the nutritional supplements and/or additional vitamin tablets to a bariatric surgery candidate or dialysis candidate for at least about 8 weeks prior to surgery or the start of dialysis, more preferably for at least about 6 weeks prior to surgery or the start of dialysis, still more preferably for at least about 4 weeks prior to surgery or the start of dialysis, and most preferably for at least about 2 weeks prior to surgery or the start of dialysis.
  • These same candidates, should they undergo surgery or dialysis may be treated with the nutritional supplement compositions in accordance with the disclosed methods following surgery or dialysis.
  • a further aspect of the present invention is a composition comprising one or more vitamins and/or minerals useful for treating nutritional deficiencies or maintaining vitamin blood serum levels in a bariatric surgery patient or a renal or dialysis patient.
  • the composition may be used in previously known regimens for satisfying nutritional needs and treatment of nutritional deficiencies, but is specifically intended to be used in the practice of the treatment regimen of the present invention described above.
  • a composition of the present invention is generally a tablet (sometimes referred to as a troche or lozenge) containing the active and non-active (i.e., biologically inert) ingredient components (sometimes referred to as excipients) as detailed herein.
  • the tablet is a rapidly dissolvable tablet containing these components, and in particular, in combination with a disintegrant or super disintegrant.
  • the rapidly dissolvable tablet comprises one or more B vitamins, and preferably two or more B vitamins.
  • the B vitamins will be selected from the group consisting of Bi (thiamine and thiamine HCI), B 2 (riboflavin), B 3 (niacin, niacinimid, nicotinic acid, and nicotinamide), B 5 (pantothenic acid and d-calcium pantothenate), B 6 (pyhdoxine, pyridoxine HCI, pyridoxal, and pyhdoxamine), B 7 (biotin, also known as Vitamin H), B 9 (folate and folic acid, also known as vitamin M), and Bi 2 (cobalamin).
  • Bi thiamine and thiamine HCI
  • B 2 riboflavin
  • B 3 niacin, niacinimid, nicotinic acid, and nicotinamide
  • B 5 pantothenic acid and d-calcium pantothenate
  • B 6
  • any one or more of the B vitamins may be in any of the numerous forms of the vitamins known in the art, including pharmaceutically acceptable salts thereof, chemically modified equivalents thereof, and mixtures thereof.
  • the selection of the specific form of any one or more of the B vitamins to be used in the composition depends upon a number of factors known to those of skill in the art, including, for example, the composition in which the vitamins are to be mixed or dissolved, the amount or concentration of the vitamins desired in the composition, the solubility of the vitamins, and the pH of the composition or resulting tablet.
  • the cobalamin may be any of a number of known cobalamin compounds, including for example, cyanocobalamin, hydroxocobalamin (vitamin Bi 2a ), hydroxocobalamin HCI, sulfate, acetate and other hydroxocobalamin salts, aquacobalamin (vitamin Bi 2 b), nithlocobalamin (vitamin Bi 2c ), methylcobalamin (methyl Bi 2 ), 5'-deoxyadenosine cobalamin (coenzyme Bi 2 ), pharmaceutically acceptable salts thereof, chemically modified equivalents thereof, and mixtures thereof.
  • the cobalamin is cyanocobalamin.
  • Bi also commonly referred to as thiamin(e), thiamine HCI, and thiamine mononitrate
  • thiamin(e) is, for example, important for functions critical for energy production and nerve transmission.
  • a common disorder resulting from vitamin Bi deficiency is termed beriberi. Symptoms of this disorder range from vague fatigue, weakness, and confusion to difficulty walking up stairs, standing on one leg, and hallucination or psychosis.
  • Vitamin Bi is typically easily absorbed by the body; however, surgical bypass of the upper small intestine eliminates some of the primary absorption sites for it.
  • ethanol is known to block the transport of Bi from the gut into the body.
  • Bi is water soluble and has no listed tolerable upper level (UL) because no evidence of oral toxicity has been seen even with doses as high as 200 mg taken for extended periods of time.
  • vitamin Bi if present, will be in an amount of about 0.375 mg to about 100 mg per tablet, preferably about 1 mg to about 50 mg per tablet, more preferably about 1.35 mg per tablet to about 2.25 mg per tablet, and most preferably in an amount of about 1.5 mg per tablet.
  • the amount of Bi present in a nutritional supplement tablet when utilized in surgical candidates may be significantly higher than it is in a tablet typically used in a post-surgery patient.
  • Bi will be in a nutritional supplement for bariathc patients in an amount of about 50 mg to about 100 mg per tablet, preferably about 75 mg to about 100 mg per tablet, more preferably about 75 mg per tablet, and most preferably in an amount of about 100 mg per tablet.
  • the amount of Bi present in a nutritional supplement for renal and dialysis patients will generally be in an amount of about 0.75 mg to about 200 mg per tablet, preferably about 0.75 mg to about 100 mg per tablet, more preferably about 1 mg to about 50 mg per tablet, still more preferably about 1 mg to about 25 mg per tablet, even more preferably in an amount of about 1.5 mg per tablet, and most preferably in an amount of about 2.0 mg per tablet.
  • B 2 (also commonly referred to as riboflavion) is, for example, important for conversion of carbohydrates into sugar. Symptoms of B 2 deficiency include fatigue, slowed growth, digestive problems, cracks and sores around the corners of the mouth, eye fatigue, and sensitivity to light. B 2 is typically readily absorbed from the upper gastrointestinal (Gl) tract; however, absorption involves active transport mechanisms and the extent of Gl absorption may be limited by the duration of contact of the drug with the specialized segment of mucosa where absorption occurs. The extent of Gl absorption of B 2 may be increased when the nutritional supplement is administered with food and may be decreased in patients with hepatitis, cirrhosis, or biliary obstruction.
  • Gl gastrointestinal
  • vitamin B 2 is a water soluble nutrient for which no tolerable upper level has been established.
  • vitamin B 2 if present, in a nutritional supplement for bariathc patients will be in an amount of about 0.45 mg to about 100 mg per tablet, preferably about 0.45 mg to about 2.25 mg per tablet, more preferably about 0.85 mg per tablet to about 1.28 mg per tablet, and most preferably in an amount of about 0.85 mg per tablet.
  • the amount of B 2 in a nutritional supplement for renal and dialysis patients will generally be in an amount of about 0.85 mg to about 200 mg per tablet, preferably about 0.85 mg to about 100 mg per tablet, more preferably about 1 mg to about 50 mg per tablet, still more preferably about 1 mg to about 25 mg per tablet, even more preferably in an amount of about 1.7 mg per tablet, and most preferably in an amount of about 2.3 mg per tablet.
  • B 3 (also commonly referred to as niacin and niacinamide), for example, converts carbohydrates into glucose and plays and important role in maintaining muscle tone along the digestive tract, as well as promoting the health of the nervous system, skin, hair, eyes, mouth, and liver. Symptoms of a B 3 deficiency include, for example, indigestion, fatigue, canker sores, vomiting, and depression. Both acid and amide forms are readily absorbed in the small intestine. Toxicity is possible; the Institute of Medicine lists 35 mg/day as the tolerable upper limit for niacin.
  • vitamin B 3 if present, in a nutritional supplement for bariatric patients will be in an amount of about 5 mg to about 50 mg per tablet, preferably about 5 mg per tablet to about 17.5 mg per tablet, more preferably about 9 mg per tablet to about 15 mg per tablet, and most preferably in an amount of about 10 mg per tablet.
  • the amount of B 3 if present, in a nutritional supplement for renal and dialysis patients will generally be in an amount of about 5 mg to about 100 mg per tablet, preferably about 5 mg to about 50 mg per tablet, more preferably about 10 mg to about 30 mg per tablet, still more preferably about 20 mg to about 30 mg per tablet, even more preferably in an amount of about 20 mg per tablet, and most preferably in an amount of about 27 mg per tablet.
  • B 5 (also commonly referred to as pantothenoic acid), for example, is a constituent of coenzyme A. It plays an important role in the metabolism of carbohydrates, proteins, and fats and is, therefore, important for the repair of all cells and tissues. It is readily absorbed in the small intestine. B 5 is a water soluble nutrient for which the Institute of Medicine does not list a tolerable upper level. Generally, vitamin B 5 , if present, in a nutritional supplement for bariatric patients will be in an amount of about 2.5 mg to about 15 mg per tablet, preferably about 4.5 mg per tablet to about 7.5 mg per tablet, and most preferably in an amount of about 5 mg per tablet.
  • the amount of B 5 in a nutritional supplement for renal and dialysis patients will generally be in an amount of about 1 mg to about 30 mg per tablet, preferably about 1 mg to about 20 mg per tablet, more preferably about 1 mg to about 10 mg per tablet, still more preferably about 2.5 mg to about 10 mg per tablet, even more preferably in an amount of about 5 mg per tablet, and most preferably in an amount of about 6.8 mg per tablet.
  • B 6 (also commonly referred to as pyhdoxine HCL) serves, for example, as a coenzyme and is involved in the metabolism of protein and carbohydrates, the production of insulin and blood cells, and the synthesis of neurotransmitters, enzymes, and prostaglandins.
  • Symptoms of B 6 deficiency are vaguely defined and include, for example insomnia, irritability, nervousness, muscle weakness, and difficulty in walking, and may result in fissures and cracking at the corners of the mouth.
  • B 6 is typically readily absorbed in the small intestine. Excess vitamin B is excreted in the urine so adequate daily intake is essential. B 6 intake at high concentrations for extended periods of time can be toxic.
  • vitamin B 6 in a nutritional supplement for bariathc patients will be in an amount of about 0.5 mg to about 50 mg per tablet, preferably about 2.25 mg per tablet to about 5 mg per tablet, more preferably about 2.25 mg per tablet to about 3.75 mg per tablet, and most preferably in an amount of about 2.5 mg per tablet.
  • the amount of B 6 in a nutritional supplement for renal and dialysis patients will generally be in an amount of about 1 mg to about 100 mg per tablet, preferably about 1 mg to about 50 mg per tablet, more preferably about 5 mg to about 25 mg per tablet, still more preferably about 10 mg to about 20 mg per tablet, even more preferably in an amount of about 10 mg per tablet, and most preferably in an amount of about 14 mg per tablet.
  • B 7 (also commonly referred to as biotin), for example, plays a role in carbohydrate, fat, and protein metabolism and is necessary for normal growth and body function. It is readily absorbed in the small intestine, and in particular in the upper part of the small intestine. B 7 is a water soluble nutrient for which the Institute of Medicine has no published tolerable upper level. Generally, vitamin B 7 , if present, in a nutritional supplement for bahatric patients will be in an amount of about 22.5 ⁇ g to about 450 ⁇ g per tablet, preferably about 135 ⁇ g per tablet to about 225 ⁇ g per tablet, and most preferably in an amount of about 150 ⁇ g per tablet.
  • the amount of B 7 in a nutritional supplement for renal and dialysis patients will generally be in an amount of about 0.001 mg to about 450 mg per tablet, preferably about 0.01 mg to about 100 mg per tablet, more preferably about 0.1 mg to about 50 mg per tablet, still more preferably about 0.3 mg to about 10 mg per tablet, even more preferably in an amount of about 0.3 mg per tablet, and most preferably in an amount of about 0.4 mg per tablet.
  • B 9 (also commonly referred to as folate or folic acid), for example, is involved in the synthesis of nucleic acids and the synthesis of methionine from homocysteine.
  • B 9 deficiencies can affect cell growth, leading to specific forms of cancer and birth defects.
  • B 9 in food must be hydrolyzed, and the best B 9 absorption occurs on an empty stomach.
  • B 9 is primarily absorbed in the jejunum, with absorption also occurring in the duodenum.
  • a zinc deficiency can contribute to B 9 deficiency.
  • the Institute of Medicine lists 1000 ⁇ g as the tolerable upper limit for folic acid and limits over the counter supplements to 800 ⁇ g.
  • vitamin B 9 if present, in a nutritional supplement for bahatric patients will be in an amount of about 100 ⁇ g to about 1000 ⁇ g per tablet, preferably about 270 ⁇ g per tablet to about 450 ⁇ g per tablet, and most preferably in an amount of about 300 ⁇ g per tablet.
  • B 9 could be present in a particular embodiment of the tablet designated for patients also taking supplemental Bi 2 (e.g., nasally administered Bi 2 ) under the supervision of medical personnel.
  • supplemental Bi 2 e.g., nasally administered Bi 2
  • such personnel could act to mitigate the risk associated with masking of the Bi 2 deficiency by B 9 , this masking effect being the primary reason for limiting the amount of B 9 in the disclosed nutritional supplement tablet.
  • the amount of B 9 in a nutritional supplement for renal and dialysis patients will generally be in an amount of about 0.1 mg to about 20 mg per tablet, preferably about 0.1 mg to about 10 mg per tablet, more preferably about 1 mg to about 10 mg per tablet, still more preferably about 2 mg to about 5 mg per tablet, even more preferably in an amount of about 2 mg per tablet, and most preferably in an amount of about 2.7 mg per tablet.
  • Bi 2 (also commonly referred to as cobalamin), for example, is required for the creation of energy from dietary fats and proteins, the production of hemoglobin, the reduction of homocysteine back to methionine, and the synthesis of s-adenosyl-methionine (SAM-e).
  • SAM-e s-adenosyl-methionine
  • a Bi 2 deficiency can result in a toxic build-up of homocysteine.
  • Absorption of Bi 2 takes place in the small intestine and generally requires the presence of intrinsic factor (IF), a protein found in the stomach.
  • IF intrinsic factor
  • Bi 2 ingested in food is generally bound by IF, the resultant complex typically reaching the intestine within 2-3 hours thereafter.
  • vitamin Bi 2 if present, in a nutritional supplement for bahatric patients will be in an amount of about 1.5 ⁇ g to about 375 ⁇ g per tablet, preferably about 110 ⁇ g per tablet to about 190 ⁇ g per tablet, and most preferably in an amount of about 125 ⁇ g per tablet.
  • the amount of Bi 2 if present, in a nutritional supplement for renal and dialysis patients will generally be in an amount of about 0.001 mg to about 100 mg per tablet, preferably about 0.002 mg to about 50 mg per tablet, more preferably about 0.005 mg to about 25 mg per tablet, still more preferably about 0.006 mg to about 10 mg per tablet, even more preferably in an amount of about 0.006 mg per tablet, and most preferably in an amount of about 0.0081 mg per tablet.
  • the rapidly dissolvable tablet typically comprises one or more non- 13 vitamins as well.
  • Those vitamins may be any such non-B vitamin, including both fat-soluble and water-soluble vitamins, but typically will be one or more vitamins selected from the group consisting of vitamin A, vitamin C, vitamin D, vitamin E, and vitamin K.
  • the tablet will comprise the non-B vitamins A, C, D, and E.
  • the non-B vitamin is vitamin C.
  • any one or more of the non-B vitamins may be in any of the numerous forms of the vitamins known in the art, such as, for example, acetate and beta-carotene (vitamin A), ascorbic acid (vitamin C), vitamin D 3 /cholecalciferol and ergocalciferol (vitamin D), and d-alpha tocopherol succinate (vitamin E), and includes pharmaceutically acceptable salts thereof, chemically modified equivalents thereof, and mixtures thereof.
  • any one or more of the non-B vitamins to be used in the composition depends upon a number of factors known to those of skill in the art, including, for example, the composition in which the vitamins are to be mixed or dissolved, the amount or concentration of the vitamins desired in the composition, the solubility of the vitamins, and the pH of the composition or resulting tablet.
  • Vitamin A also commonly referred to as vitamin A acetate, retinyl palmitate, retinyl acetate, or its provitamin equivalent ⁇ -carotene & other carotenoids
  • Vitamin A deficiency can cause blindness, skin irritation, infection, and poor wound healing.
  • Retinol absorption of vitamin A tends to be much more efficient than carotenoid absorption.
  • Retinal formed from retinol via zinc is critical to night vision; therefore, low zinc status can decrease night vision without the presence of a true vitamin A deficiency.
  • vitamin A plays a role in the transport of iron into hemoglobin and red blood cell formation, a vitamin A deficiency can contribute to anemia.
  • the Institute of Medicine lists 3000 ⁇ g/day (10,000 lU/day) as the tolerable upper limit.
  • vitamin A if present, will be in an amount of about 875 IU per tablet to about 7300 IU per tablet as preformed vitamin A, pro vitamin A, or a mixture thereof, preferably about 2250 IU per tablet to about 4125 IU per tablet as preformed vitamin A, pro vitamin A, or a mixture thereof, and most preferably in an amount of about 2500 IU per tablet as preformed vitamin A, pro vitamin A, or a mixture thereof.
  • Vitamin C also commonly referred to as ascorbic acid or sodium ascorbate
  • Vitamin C is, for example, important for the manufacture of collagen, wound healing, a healthy immune and nervous system, adrenal hormone production, and as an antioxidant to help prevent disease. Absorption generally occurs in the intestine.
  • the Institute of Medicine lists 2000 mg/day as the tolerable upper limit.
  • vitamin C if present, will be in an amount of about 15 ⁇ g to about 1000 ⁇ g per tablet, preferably about 15 ⁇ g per tablet to about 120 ⁇ g per tablet, more preferably about 27 ⁇ g per tablet to about 45 ⁇ g per tablet, and most preferably in an amount of about 30 ⁇ g per tablet.
  • the vitamin C is present both in the form of ascorbic acid and sodium ascorbate.
  • the ascorbic acid may generally be present in an amount of about 1 mg to about 100 mg per tablet, preferably about 1 mg to about 50 mg per tablet, more preferably about 5 mg to about 25 mg per tablet, still more preferably about 10 mg to about 20 mg per tablet, even more preferably in an amount of about 18 mg per tablet, and most preferably in an amount of about 24 mg per tablet
  • the sodium ascorbate may generally be present in an amount of about 1 mg to about 100 mg per tablet, preferably about 5 mg to about 75 mg per tablet, more preferably about 10 mg to about 50 mg per tablet, still more preferably about 35 mg to about 50 mg per tablet, even more preferably in an amount of about 42 mg per tablet, and most preferably in an amount of about 57 mg per tablet.
  • Vitamin D also commonly referred to as cholecalciferol or ergocalciferol
  • Vitamin D is, for example, important for the absorption of calcium for bone health. In addition, it may play a role in immunity, diabetes, and heart health. Absorption of dietary vitamin D takes place in the upper part of the small intestine, generally with the aid of bile salts. D 3 (cholecalciferol) is considered the most potent form. The Institute of Medicine lists 2000 IU/day as the tolerable upper limit.
  • vitamin D if present, will be in an amount of about 100 IU per tablet to about 1000 IU per tablet, preferably about 100 IU per tablet to about 660 IU per tablet, more preferably about 360 IU per tablet to about 660 IU per tablet, and most preferably in an amount of about 400 IU per tablet.
  • Vitamin E also commonly referred to as d-Alfa tocopheryl acid succinate (natural form), dl-alpha tocopheryl acid succinate (synthetic form - only d active), and tocothenols (less active form)
  • Vitamin E is readily absorbed, with the natural and d-alpha tocopherol forms being absorbed better than the synthetic dl-alpha tocopheryl acid succinate form.
  • the Institute of Medicine lists 1500 IU/day as the tolerable upper limit. Impaired thyroid function can result from the long term intake of 600 IU/day.
  • vitamin E if present, will be in an amount of about 7.5 IU per tablet to about 750 IU per tablet, preferably about 15 IU per tablet to about 300 IU per tablet, more preferably about 13.5 IU per tablet to about 24.75 IU per tablet, and most preferably in an amount of about 15 IU per tablet.
  • non-B vitamins such as for example, vitamin K
  • Concentrations and forms of such vitamins for such a tablet are readily determined by one of ordinary skill in the art according to factors well known in the medical arts.
  • the rapidly dissolvable tablet typically, although not necessarily, comprises one or more minerals as well, particularly when administered as a composition for providing nutritional supplementation to bariathc patients.
  • Those minerals may include any minerals generally known in the art to be dietary minerals which are beneficial to human health, and in particular, those often referred to as essential minerals which are necessary for ideal human health.
  • Examples of minerals that may be present in the tablet include, for example, boron, bromine, cadmium, calcium, chloride, chromium, cobalt, copper, fluoride, iodine, iron, magnesium, manganese, molybdenum, nickel, phosphorous, potassium, selenium, silicon, sodium, tin, tungsten, vanadium, and zinc.
  • the tablet will comprise one or more minerals selected from the group consisting of chromium, copper, iron, manganese, molybdenum, selenium, and zinc. Any one or more of the minerals may be in any of the numerous forms known in the art. By way of example, minerals may be in the form of an amino acid chelate with respect to chromium, molybdenum, and selenium, a citrate with respect to copper, manganese, and zinc, and a fumarate with respect to iron, and includes pharmaceutically acceptable salts thereof, chemically modified equivalents thereof, and mixtures thereof.
  • any one or more of the minerals to be used in the composition depends upon a number of factors known to those of skill in the art, including, for example, the composition in which the minerals are to be mixed or dissolved, the amount or concentration of the minerals desired in the composition, the solubility of the minerals, and the pH of the composition or resulting tablet.
  • the tablet of the present invention comprises the minerals chromium, copper, iron, manganese, molybdenum, selenium, and zinc, and is free of therapeutic amounts of calcium and/or magnesium. It has been determined that the exclusion of therapeutic quantities of calcium and/or magnesium reduces tablet size, and optimizes dissolution rate, taste, and mouth feel of the tablet. More particularly, exclusion of therapeutic quantities of calcium and/or magnesium allows inclusion of sufficient quantities of non-active ingredients (e.g., directly compressible mannitol) necessary to provide a rapidly dissolvable tablet.
  • non-active ingredients e.g., directly compressible mannitol
  • exclusion of therapeutic amounts of calcium from the rapidly dissolvable tablet, and oral administration of the same in a second, separate tablet, may also enhance overall calcium absorption, as the iron in the rapidly dissolvable tablet can potentially interfere with calcium absorption if both ingredients are administered in the same tablet.
  • sub-therapeutic amounts of calcium and/or magnesium may be present, for example, as a cation associated with other ingredients in salt form, such as, for example, magnesium stearate used as a lubricant or calcium pantothenate.
  • the tablet of the present invention is free of therapeutic quantities of phosphorous, potassium, and/or sodium, and more preferably essentially free of phosphorous, potassium, and/or sodium. Because renal and dialysis patients have compromised or failed kidney function, concentrations of these minerals in the blood as a result of consumption of normal dietary amounts of the same would result in excess blood serum concentrations of these minerals. Because the excess amounts can only be removed during dialysis treatments (as opposed to continually when kidney function is normal), serious health risks and dietary complications (i.e., increased thirst, resulting in increased fluid intake which is also severely restricted in the diet of renal and dialysis patients) can result. Thus, patients already on a diet restricting the intake of phosphorous, potassium, and/or sodium, as well as fluids, need nutritional supplementation that is substantially or completely free of these minerals.
  • Chromium also commonly referred to as chromium chelate
  • Chromium chelate aids transport of glucose into cells and enhances the effect of insulin in glucose utilization.
  • a chromium deficiency can result in reduced tissue sensitivity to glucose similar to that seen patients suffering from diabetes, numbness in extremities, and disturbances of glucose, fat, and protein metabolism.
  • Chromium is readily absorbed, with organic chromium being absorbed more efficiently than inorganic chromium. There is little known about chromium toxicity, although there is some evidence that doses above 250 ⁇ g can cause adverse reactions. Dietary forms of the mineral, however, have very low toxicity.
  • chromium if present, will be in an amount of about 30 ⁇ g to about 125 ⁇ g per tablet, preferably about 30 ⁇ g per tablet to about 60 ⁇ g per tablet, more preferably about 42 ⁇ g per tablet to about 78 ⁇ g per tablet, and most preferably in an amount of about 60 ⁇ g per tablet.
  • Copper also commonly referred to as copper citrate, cupric oxide, copper amino acid chelate, copper gluconate, and copper sulfate
  • copper citrate cupric oxide, copper amino acid chelate, copper gluconate, and copper sulfate
  • copper sulfate is, for example, important for normal metabolism; healthy bones, joints, skin, and blood vessels; a healthy nervous, cardiovascular, and immune systems; the formation of hemoglobin in red blood cells; and antioxidant action. It is absorbed in the stomach and small intestine.
  • the Institute of Medicine lists 10 mg/day as the tolerable upper limit.
  • copper if present, will be in an amount of about 0.5 mg to about 5 mg per tablet, preferably about 0.7 mg per tablet to about 2 mg per tablet, more preferably about 0.7 mg per tablet to about 1.3 mg per tablet, and most preferably in an amount of about 1 mg per tablet.
  • copper citrate as opposed to the chelate form, is used as the copper source to improve the taste of the tablet.
  • Iron also commonly referred to as ferrous (Fe 2+ ) fumarate and carbonyl iron
  • Fe 2+ ferrous fumarate and carbonyl iron
  • An iron deficiency can result in anemia, hair loss, shortness of breath, and a swollen tongue.
  • the Institute of Medicine lists 45 mg/day as the tolerable upper limit. Acute toxicity can occur at intake levels of 40 mg/Kg, and a single dose 200+ mg/Kg can be fatal.
  • iron if present, will be in an amount of about 2.8 mg to about 18 mg per tablet, preferably about 2.8 mg per tablet to about 9 mg per tablet, more preferably about 2.8 mg per tablet to about 5.2 mg per tablet, and most preferably in an amount of about 4 mg per tablet.
  • the amount of iron may also be increased to an amount of about 9 mg per tablet in order to achieve the FDA RDI of 18 mg per day. This may be accomplished utilizing the forms of iron disclosed herein.
  • iron has the potential to impart a less than pleasant taste to the tablet and can also lead to other minor side effects such as stomach irritation
  • increasing the amount of iron to a still more preferred amount of about 9 mg per tablet may be more readily achieved if the form of iron used is well suited to this type of tablet, such as, for example, forms of iron with very little taste or that are gentler on the stomach.
  • Manganese also commonly referred to as manganese citrate, manganese amino acid chelates, manganese sulfate, and manganese gluconate
  • manganese citrate also commonly referred to as manganese citrate, manganese amino acid chelates, manganese sulfate, and manganese gluconate
  • the Institute of Medicine lists 11 mg/day as the tolerable upper limit.
  • manganese if present, will be in an amount of about 0.5 mg to about 5.5 mg per tablet, preferably about 0.7 mg per tablet to about 2 mg per tablet, more preferably about 0.7 mg per tablet to about 1.3 mg per tablet, and most preferably in an amount of about 1 mg per tablet.
  • Molybdenum also commonly referred to as molybdenum chelate, sodium molybdate
  • molybdenum chelate sodium molybdate
  • Deficiency is rare, as molybdenum is readily absorbed from dietary intake. Molybdenum, does however, compete with copper at absorption sites and, therefore, can inhibit copper absorption at higher doses.
  • the Institute of Medicine lists 2000 ⁇ g/day as the tolerable upper limit; however, concentrations above 500 ⁇ g/day have been found to cause significant losses of copper.
  • molybdenum if present, will be in an amount of about 11.25 ⁇ g to about 1000 ⁇ g per tablet, preferably about 22.5 ⁇ g per tablet to about 150 ⁇ g per tablet, more preferably about 26.25 ⁇ g per tablet to about 48.75 ⁇ g per tablet, and most preferably in an amount of about 37.5 ⁇ g per tablet.
  • Selenium also commonly referred to as selenium Citrate, sodium selenite, and l-selenomethionine
  • Selenium is, for example, important to thyroid activity and may play an important role in immune function and cancer prevention.
  • Organic selenium is absorbed more efficiently than inorganic forms.
  • the Institute of Medicine lists 400 ⁇ g/day as the tolerable upper limit; however, a study of healthy men fed diets with approximately 300 ⁇ g of selenium developed clinical hypothyroidism and weight gain after only 99 days.
  • selenium if present, will be in an amount of about 13 ⁇ g to about 200 ⁇ g per tablet, preferably about 13 ⁇ g per tablet to about 150 ⁇ g per tablet, more preferably about 19.25 ⁇ g per tablet to about 35.75 ⁇ g per tablet, and most preferably in an amount of about 27.5 ⁇ g per tablet.
  • Zinc also commonly referred to as zinc citrate, zinc oxide, zinc methionine, zinc gluconate, zinc sulfate, zinc picolinate, and chelated zinc
  • Zinc is, for example, important for growth and development, skin health, host defense, immunity, protein & cell membrane structure, and genetic transcription.
  • zinc-dependant enzymes catalyze digestion, immune function, and antioxidant activity.
  • Zinc deficiency symptoms include loss of smell, abnormal or diminished sense of taste, poor wound healing, skin rashes, and thinning hair.
  • Zinc is readily absorbed by the body, with organic forms of zinc being better absorbed than other forms.
  • the Institute of Medicine lists 40 mg/day as the tolerable upper limit.
  • Acute toxicity can occur at doses as low as 30 mg/day, but is more common with doses exceeding 100 mg/day.
  • zinc if present, will be in an amount of about 3.75 mg to about 20 mg per tablet, preferably about 3.75 mg per tablet to about 15 mg per tablet, more preferably about 5.25 mg per tablet to about 9.75 mg per tablet, and most preferably in an amount of about 7.5 mg per tablet.
  • zinc is present in an amount of about 15 mg, and in another embodiment in an amount of about 20.25 mg.
  • zinc citrate as opposed to the chelate form, is used as the zinc source to improve the taste of the tablet.
  • Additional minerals such as for example, boron, bromine, cadmium, calcium, chloride, cobalt, fluoride, iodine, magnesium, nickel, phosphorous, potassium, silicon, sodium, tin, tungsten, and vanadium may also be present in the rapidly dissolving tablets disclosed herein. Concentrations and forms of each of these minerals for such a tablet are readily determined by one of ordinary skill in the art according to factors well known in the medical arts. In particular, forms of the rapidly dissolvable tablet intended for providing nutritional supplementation to renal or dialysis patients will generally be free of phosphorous, potassium, and/or sodium.
  • magnesium, calcium, or a combination of magnesium and calcium are also included in the tablet.
  • magnesium, if present in a therapeutic quantity is present as magnesium citrate in an amount of about 12.5 mg to about 400 mg per tablet, preferably about 12.5 mg to about 200 mg per tablet, more preferably about 12.5 mg per tablet to about 25 mg per tablet, and most preferably in an amount of about 25 mg per tablet.
  • calcium, if present in a therapeutic quantity is present as calcium citrate in an amount of about 25 mg to about 1000 mg per tablet, preferably about 200 mg per tablet to about 600 mg per tablet, more preferably about 500 mg per tablet to about 600 mg per tablet, and most preferably in an amount of about 600 mg per tablet.
  • Additional nutrients such as, for example, choline, inositol, bioflavinoids (such as citrus fruit peel bioflavinoids), arabinogalactans, probiotics (such as lactobacillus acidophilus), ginseng, ginko, lutein, lycopene, phytosterols, and other nutrients commonly found in multi-vitamins, may also be present in the rapidly dissolving tablets disclosed herein. Concentrations and forms of such nutrients for such a tablet are readily determined by one of ordinary skill in the art according to factors well known in the medical arts.
  • the active ingredient component of the rapidly dissolvable tablet is particularly suited for providing nutritional supplementation to a bariathc patient or candidate and has the formulation disclosed in Table 1.
  • the active ingredient component of the rapidly dissolvable tablet is particularly suited for providing nutritional supplementation to a renal or dialysis patient or candidate and has the formulation disclosed in Table 2. Table 2. Specific active ingredient component formulation of rapidly dissolving tablet for renal or dialysis patents
  • the composition may be sugar free.
  • Sugar free is generally understood to mean that the tablet or daily dose (e.g., two tablets) contains less than 0.5 g of sugars per reference amount customarily consumed and per label serving (e.g., one or two tablets).
  • Sugar free as used herein is understood to include a nutritional supplement composition that contains a sugar alcohol (also known as a polyol, a polyhydhc alcohol, or a polyalcohol), such as, for example, glycol, glycerol, erythritol, xylitol, mannitol, sorbitol, malitol, and lactitol, and other compounds having the general formula H(HCHO) n +iH (as opposed to the formula H(HCHO) n H.of the related sugar) and which generally do not result in a typically change in blood glucose levels associated with consumption of a sugar.
  • a sugar alcohol also known as a polyol, a polyhydhc alcohol, or a polyalcohol
  • a sugar alcohol also known as a polyol, a polyhydhc alcohol, or a polyalcohol
  • a sugar alcohol also known as a polyol, a polyhydhc alcohol, or
  • the rapidly dissolvable tablets of the present invention also contain non-active ingredients (sometimes referred to herein as "non-active components” or as “excipients”) that allow for the active ingredients to be formulated as a tablet that rapidly dissolves in the mouth of a patient upon oral administration.
  • non-active components include, for example, one or more of a diluent or filler, a binder, a disintegrant, a lubricant, a sweetener, and a flavoring agent.
  • certain non-active ingredients may have multiple functions, such as filler, binder, and disintegrant or binder, filler, and sweetener.
  • the rapidly dissolvable tablet of the present invention comprises a rapidly dissolvable sugar or sugar alcohol that serves as a binder and filler.
  • This sugar or sugar alcohol may also serve as a sweetener, aiding in masking the otherwise unpleasant tastes of the active ingredient component contained in the tablet.
  • sugars or sugar alcohols include, for example, mannitol, lactose, sucrose, maltose, dextrose, sorbitol, xylitol, maltitol, lactitol, and maltodexthns. Mannitol and other similar compounds having a negative heat of solution are preferred because they provide a particularly pleasant sensation enhancing the organoleptic experience of ingesting the described tablet.
  • the rapidly dissolvable sugar or sugar alcohol binder and filler (sometimes referred to herein as a "binder/filler”) is a directly-compressible, water-soluble carbohydrate.
  • directly compressible mannitol may be used.
  • An example of a product containing directly compressible mannitol is LUDIFLASH® (BASF, Switzerland), and in one preferred embodiment, the rapidly dissolvable sugar or sugar alcohol binder and filler is a directly-compressible, water-soluble carbohydrate, particularly mannitol, and more particularly mannitol present in LUDIFLASH®.
  • the directly compressible mannitol is Roquette's PEARLITOL® 100 SD as described in U.S. patent No. 5,573,777, the content of which is hereby incorporated herein by reference.
  • the tablet in accordance with the present invention generally comprises between about 5% and about 80% of the rapidly dissolvable sugar or sugar alcohol binder and filler based on the weight of the tablet. More preferably, the amount of such filler will range from about 50% to about 80% by weight based on the tablet, still more preferably from about 70% to about 80% by weight, and most preferably from about 75% to about 80% by weight of the tablet.
  • the rapidly dissolvable tablet of the present invention also preferably comprises a disintegrant or a super disintegrant to aid in the rapid dissolution of the tablet in the mouth of a patient upon oral administration of the tablet.
  • Classical disintegrants include, for example, starches, pre-gelatinized starches, alginates, low-substituted hydroxypropylcellulose, and microcrystalline cellulose.
  • Super disintegrants include, for example, sodium starch glycolate (an example of a crosslinked starch), croscarmellose and croscarmellose sodium (also known as crosslinked sodium carboxymethyl cellulose) (examples of a crosslinked cellulose), crospovidone (polyvinyl pyrrolidone (“PVP”)) (an example of a crosslinked polymer), gellan gum, and Xanthan SM, and are generally water insoluble. While they add to the rapid disintegration of the formulation, their inclusion can also add to the total content of insoluble ingredients making it more difficult to strike a balance between disintegration/dissolution speed and the resulting organoleptic sensation.
  • sodium starch glycolate an example of a crosslinked starch
  • croscarmellose and croscarmellose sodium also known as crosslinked sodium carboxymethyl cellulose
  • crospovidone polyvinyl pyrrolidone
  • gellan gum and Xanthan SM
  • the amount of disintegrant or super disintegrant will range from about 0.5% to about 10% by weight based on the weight of the tablet, preferably from about 1 % to about 10% by weight based on the weight of the tablet, and more preferably from about 1 % to about 5%.
  • An amount of disintegrant or super disintegrant that is 5% or less by weight of the tablet is most preferred.
  • polyvinyl pyrrolidone a composition comprising polyvinyl pyrrolidone, croscarmellose, croscarmellose sodium, sodium starch glycolate, gellan gum, or Xanthan SM, a combination of any one of these compounds, or a composition comprising any one or more of these compounds are the preferred super disintegrants, with polyvinyl pyrrolidone or a composition comprising polyvinyl pyrrolidone being the most preferred super disintegrant, other useful but lesser effective disintegrants include microcrystalline cellulose and starch.
  • the type and quantity of non-active ingredients are selected so as to provide a nutritional supplement tablet that dissolves in the mouth of the patient in less than about 90 seconds, preferably in less than about 80 seconds, more preferably in less than about 70 seconds, still more preferably in less than about 60 seconds, even more preferably in less than about 45 seconds, and most preferably in less than about 30 seconds after administration of the tablet.
  • the dissolution rate is attained without the contemporaneous administration of exogenous liquids to the patient.
  • the tablet dissolves upon contact with saliva and agitation in the buccal cavity of the patient (e.g., by movement of the tongue) without mastication of the tablet. That is, the tablet is held in the mouth of the patient, similar to a lozenge, and not chewed.
  • the binder/filler and the disintegrant or super disintegrant may be provided as a single ingredient component.
  • the mannitol binder and filler is provided as a mixture that also contains a percentage of polyvinyl pyrrolidone.
  • the binder and filler and super disintegrant may be provided as a composition that comprises about 80% to 100%, and preferably about 90% by weight mannitol, about 0.5% to about 5%, and preferably about 5% by weight polyvinyl acetate, and about 3% to about 7%, and preferably about 5% by weight crospovidone (polyvinyl pyrrolidone).
  • Such a composition is generally in the form of a co-processed agglomerate, typically comprising d-mannitol, crospovidone, polyvinyl acetate, and povidone, and having exceptional tableting and disintegration properties that are superior to the simple mixing of a binder/filler and disintegrant or super disintegrant, and will have a controlled particle size distribution, particle structure, high bulk density, and good flowability.
  • a combined binder/filler and disintegrant or super disintegrant composition may have a particle size distribution wherein particles having a size of greater than about 0.4 mm may constitute a maximum of 20% of the composition; particles having a size less than about 0.2 mm may constitute a maximum of about 90% to a minimum of about 45% of the composition; and particles having a size of less than about 0.063 mm may constitute a maximum of about 90% to a minimum of about 45% of the composition.
  • the combined binder/filler and disintegrant or super disintegrant component comprises between about 50% to about 80% by weight of the tablet, still more preferably from about 70% to about 80% by weight, and most preferably from about 75% to about 80% by weight of the tablet.
  • particle size of all components of the tablet may generally be of a size that allows for direct compression of all components, and the desired hardness, friability, and dissolution or disintegration time.
  • such components may be of a similar size, such as for example, within two orders of magnitude.
  • the tablet of the present invention may further comprise a lubricant.
  • the lubricant aids in removal of the tablet from the device utilized to make the tablet, such as, for example, a tablet press.
  • lubricants include stearic acid, magnesium stearate, and combinations of thereof.
  • the lubricant will be present in an amount sufficient to enable removal of the tablet from the tablet press, but in an amount sufficiently minimal enough to not negatively interfere with the
  • the lubricant component of the tablet may comprise from about 0.5% to about 5% by weight of the tablet. More preferably, the lubricant comprises from about 1 % to about 3% by weight of the tablet.
  • the lubricant is magnesium stearate and comprises about 1 % by weight of the tablet.
  • the lubricant is magnesium stearate and comprises about 2.4% by weight of the tablet.
  • the lubricant is stearic acid and comprises about 1 % by weight of the tablet.
  • the lubricant is a combination of magnesium stearate and stearic acid and comprises about 2% by weight of the tablet.
  • the lubricant is a combination of magnesium stearate and stearic acid and comprises about 3.4% by weight of the tablet.
  • the tablet of the present invention may further comprise a sweetener or flavoring agent.
  • sweetener or flavoring agent mask the otherwise unpleasant taste of the active ingredient component, giving the composition a sweet and pleasant flavor or taste.
  • examples of such ingredients include, for example, mannitol, sucralose, xylitol, potassium acesulfame, fructose, ascorbic acid, and fruit punch or orange flavorings.
  • the sweetener or flavoring agent will be present in an amount sufficient to provide a pleasing taste to the tablet, thereby improving patient compliance with the administration regimen, but not in an amount that negatively interferes with the manufacture or desired disintegration characteristics of the tablet.
  • these ingredients will comprise about 0.5% to about 5% by weight of the tablet.
  • the rapidly dissolvable tablet has the non-active ingredient component formulation disclosed in Table 3 and is suitable for preparation of a rapidly dissolving tablet for bahatric patients.
  • the rapidly dissolvable tablet has the non-active ingredient component formulation disclosed in Table 4 and is suitable preparation of a rapidly dissolving tablet for renal or dialysis patients.
  • Table 3 Tablet Excipients
  • the rapidly dissolvable nutritional composition in a two tablet format suitable for bahatric patients comprises the active and non-active ingredient component formulation disclosed in Table 4.
  • the rapidly dissolvable nutritional composition in a single tablet format suitable for renal or dialysis patients comprises the active and non- active ingredient component formulation disclosed in Table 5.
  • the rapidly dissolvable nutritional composition in a single tablet format suitable for renal or dialysis patients comprises the active and non-active ingredient component formulation disclosed in Table 6.
  • the embodiments in Tables 6 and 7 are demonstrated as a 45 kg batch in Figure 8. Table 5. Active and non-active ingredient component formulation of one embodiment of the rapidly dissolvable tablet
  • the rapidly dissolvable nutritional composition in a two tablet format suitable for a bariatric patient comprises the active and non-active ingredient formulation disclosed in Table 9.
  • Each tablet of this embodiment is designed to have a smooth mouth feel and is approximately 1250 mg in weight with an off white color and fruit flavor, with a standard dosage being two tablets per day.
  • the rapidly dissolvable nutritional composition in a two tablet format i.e., a daily does is to be administered as two tablets
  • suitable for bahatric patients comprises the active and non-active ingredient formulation disclosed in Table 10.
  • the rapidly dissolving nutritional tablet will generally have a pH that is not excessively basic, and more preferably a pH that is acidic. Accordingly, in a preferred embodiment, the rapidly dissolving nutritional supplement will exhibit a pH that is from about 3 to about 10. In accordance with a more preferred embodiment, the rapidly dissolving nutritional tablet exhibits a pH of less than about 7 and more preferably, from about 3 to about 6, still more preferably from about 4 to about 5, and most preferably about 4.5.
  • the pH of the nutritional tablet can be adjusted by proper selection of the forms of active and non- active ingredients, e.g., selection of citrate forms instead of carbonate forms of the various ingredients.
  • pH of the rapidly dissolving nutritional tablet is determined by dissolving a tablet in approximately 100 ml_ of purified water and measuring the pH of the resulting solution (e.g., using a pH meter).
  • the rapidly dissolvable nutritional tablet may be prepared in accordance with known manufacturing techniques. For example, a premix of the active ingredient component may be dry mixed with the non-active ingredient component in a suitable blender to form a pre-tablet mixture. This mixture is then introduced into a suitable tableting device and compressed to form the tablet.
  • the manufacturing process utilizes the following raw materials (Table 11 ) and the following equipment (Table 12):
  • Blending and formation of the tablet may be accomplished according to the following blending and tableting process.
  • FIG. 1 An example of a process for manufacturing a rapidly dissolvable tablet in accordance with the present invention is shown in Figure 1.
  • the required non-active raw materials (see Table 11 ) are dispensed into a blender.
  • the binder/filler and disintegrant e.g., LUDIFLASH®
  • LUDIFLASH® the binder/filler and disintegrant
  • the order of addition may be as desired, but generally is determined based on efficiency of manufacturing.
  • the non-active raw materials are blended for an amount of time sufficient to provide a substantially homogeneous mixture (e.g., about 5 minutes).
  • the active ingredient component may then be added to the non-active raw material mixture as a premix and further blended for an amount of time to again provide a substantially homogeneous mixture (e.g., about 10 minutes).
  • the remainder of the binder/filler and disintegrant e.g., LUDIFLASH®
  • LUDIFLASH® disintegrant
  • the final mixture is fed to a tablet press.
  • the target weight of each tablet is approximately 1250 mg +/- 50 mg. In one embodiment, the target hardness will be about 8 kp.
  • the tablets exiting the press are preferably dedusted before storage or packaging in bulk.
  • the rapidly dissolving tablet of the present invention must not only dissolve rapidly upon administration to the patient, but it must also be sufficiently attrition-resistant and capable of withstanding packaging and shipment. Accordingly, the rapidly dissolving tablet preferably exhibits a hardness of about 3 kp to about 12 kp, more preferably about 6 kp to about 10 kp, and most preferably about 8 kp.
  • the rapidly dissolvable tablet may exhibit a range of different friabilities depending in large part on the manner of packaging in which the tablets will be placed for storage, and in particular for shipping, and/or sale. Generally, the tablets will exhibit a friability of less than about 5%, preferably less than about 4%, more preferably less than about 3%, still more preferably less than about 2%, and most preferably less than about 1 %, particularly if the tablets are manufactured for multi-dose packaging (e.g., multiple tablets packaged in a typical plastic bottle for pills or tablets).
  • the friability of the tablets would tend to be lower (e.g., less than about 2% friability and more preferably less than about 1 % friability).
  • the tablets may exhibit a friability from about 5% to about 75%, more preferably about 5% to about 50%, still more preferably about 5% to about 25%, and most preferably about 5% to about 10%, particularly if the tablets are manufactured for single dose packaging (e.g., tablets packaged in a typical blister pack used for pills or tablets).
  • tablets packaged in such a fashion may also have a lower friability, such as, for example, less than about 4% friability, preferably between about 2% and about 4% friability, and more preferably between about 3% and about 4% friability.
  • the exact hardness and/or friability of the tablet may be adjusted by altering the compression force of the tableting press used in the tablet manufacturing process, as well as the tablet formulation (i.e., the type and amount of active and non-active ingredients), the tablet hardness, and the friability. Tableting pressure may be adjusted by one skilled in the art based on the particular tableting apparatus being used to achieve the desired tablet hardness and friability.
  • the purpose of this example is to characterize the durability of the nutritional supplement tablet over a range of hardness levels when the non-active ingredient component utilizes a binder/filler that is separate from the disintegrant.
  • Tablets utilized for this example were manufactured according to the process described above and utilizing the formulation of Table 10. Specifically, the required non-active raw materials of Table 10 were dispensed into a 5 cubic ft. V blender. Only a portion of the binder/filler (i.e., the mannitol in the form of Roquette's PEARLITOL® 100 SD) was initially mixed with the other non-active raw materials. The non-active raw materials were blended until they appeared to be well mixed (i.e., for 5 minutes) in a V blender. The active ingredient components listed in Table 9 were then added to the non-active raw material mixture as a premix and further blended until it appeared to be well mixed (i.e., for 5 minutes).
  • the binder/filler i.e., the mannitol in the form of Roquette's PEARLITOL® 100 SD
  • the active ingredient components listed in Table 9 were then added to the non-active raw material mixture as a premix and further blended until it appeared to be well mixed (i.
  • the remainder of the binder/filler i.e., the mannitol in the form of Roquette's PEARLITOL® 100 SD
  • the final mixture was fed into a Manesty Express Rotary 20 station tablet press and pressed into tablets having an approximate weight of 1020 mg +/- 50 mg. Tablets having a target hardness of 0.5 kp, 1.0 kp, 2.0 kp, 3.0 kp, 4.0 kp, 6.0 kp, and 8.0 kp were produced by adjusting the tableting pressure to achieve the desire tablet hardness.
  • Tablets of various hardnesses were tested to determine the amount of time required for the tablet to disintegrate.
  • the tablet was held in the mouth of the test patient similar to a lozenge so that it could be dissolved by the patient's saliva and agitation in the mouth (e.g., by movement of the tongue) without mastication of the tablet.
  • Friability was calculated as percent loss for each level using a standard friability apparatus for 100 rotations over 4 minutes.
  • Tablet durability was tested using a ship test. For each target hardness level, one or two bottles of 60 tablets each were utilized. The tablets were dedusted, weighed, placed in bottle with rayon and desiccant (except for 0.5 kp and 1.0 kp, which did not have sufficient room to place rayon or desiccant in the bottle). Each bottle was packaged in a 12-unit carton for shipping, submitted for ASTM D 4169 schedule 1 testing, removed from bottle, dedusted, and reweighed to determine percent loss for each bottle of tablets.
  • the hardness of each level was tested with a hardness tester (e.g., Pharmatron Hardness Tester, Dr. Schleuniger Pharmatron Inc, Manchester, NH) at the following time points: day of manufacture, 24 hours post-manufacture, 3 days post manufacture, and 7 days post manufacture.
  • a hardness tester e.g., Pharmatron Hardness Tester, Dr. Schleuniger Pharmatron Inc, Manchester, NH
  • Table 13 contains tablet hardness testing information from this study. Average tablet hardness is illustrated in Figure 2. The tablet hardness determination from this study should only be used to determine hardness levels to the nearest whole number kp value, due to the fluctuation in tablet hardness values.
  • Table 14 contains oral disintegration times for tablets from this study. Average oral disintegration times are illustrated in Figure 3. The desired oral disintegration target of 30 - 90 seconds in the mouth was achieved for tablets with a hardness of 2.0 kp or less. The levels of hardness of 3.0 - 6.0 kp provided tablets outside this range by up to 20 seconds, while tablets with a hardness of 8.0 kp provided tablets outside this range by 90 seconds.
  • Table 15 contains results of the friability test as a percent loss. Friability as average percent loss is illustrated in Figure 4. Hardness values of less than 3 kp yielded friability results above 5%. A hardness value of 8 kp was required to reach a friability level of ⁇ 1 %.
  • Table 16 contains the results of the ship test from this study. Percent tablet loss as a function of tablet hardness is illustrated in Figure 5. There was a 5% or greater loss over all tablet hardnesses during the ship test.
  • the packaging configuration studied in this protocol multi-dose packaging containing more than one tablet per container
  • single dose packaging such as, for example, in a blister pack
  • Table 17 contains tablet hardness for 24 hour, 3 day, and 7 day post- production tablets. This data is illustrated in Figure 6. Tablet hardness remains constant at least up to one week postproduction over all tested hardness levels. Table 17. Results of Tablet Hardness Over Time Testing
  • Table 18 contains the results of the simulated patient use test from this study. Percent tablet weight loss as a function of tablet hardness is illustrated in Figure 7. Tablet hardness levels of 3 kp or greater experienced less than 1 % loss when subjected to simulated patient use.
  • Tablets manufactured with the formulation of Table 10 do not allow for both an average oral disintegration time of 30 to 90 seconds and a friability that allows for multi-dose packaging (although they may well allow for an average oral disintegration time of 30 to 90 seconds and a friability that allows for single dose (e.g., blister) packaging).
  • Tablet hardness testing has an associated percent error, which limits hardness determination to ⁇ 1 kp at best. The variability increases predictably as the hardness value increases.
  • the purpose of this example is to characterize the durability of the nutritional supplement tablet over a range of hardness levels when the non-active ingredient component utilizes a binder/filler and disintegrant that are a single component (such as, for example, LUDIFLASH® with KOLLIDON®).
  • Tablets utilized for this example were manufactured according to the process described above and exemplified, for example, in Figure 1 utilizing the formulation of Table 9. Specifically, the required non-active raw materials of Table 9 were dispensed into a 5 cubic ft. V blender. Only a portion of the binder/filler and disintegrant (i.e., the LUDIFLASH® with KOLLIDON®) was initially mixed with the other non-active raw materials. The non-active raw materials were blended until they appeared to be well mixed (i.e., for 5 minutes) in a V blender. The active ingredient components listed in Table 9 were then added to the non-active raw material mixture as a premix and further blended until it appeared to be well mixed (i.e., for 5 minutes).
  • the binder/filler and disintegrant i.e., the LUDIFLASH® with KOLLIDON®
  • the remainder of the binder/filler i.e., the LUDIFLASH® with KOLLIDON®
  • the remainder of the binder/filler was added to the mixture in the blender, and this final mixture was blended until it appeared to be well mixed (i.e., for 10 minutes).
  • the final mixture was fed into a Manesty Express Rotary 20 station tablet press and pressed into tablets having an approximate weight of 1250 mg +/- 50 mg. Tablets having a target hardness of 6.0 kp, 8.0 kp, and 10 kp were produced by adjusting the tableting pressure to achieve the desire tablet hardness.
  • Tablets of various hardnesses were tested to determine the amount of time required for the tablet to disintegrate.
  • the tablet was held in the mouth of the test patient similar to a lozenge so that it could be dissolved by the patient's saliva and agitation in the mouth (e.g., by movement of the tongue) without mastication of the tablet.
  • Friability was calculated as percent loss for each level using a standard friability apparatus for 100 rotations over 4 minutes.
  • Tablet durability was tested using a ship test. For each level, four bottles of 60 tablets each were dedusted, weighed, placed in a bottle with rayon, packaged in a 12 unit carton for shipping, submitted for ASTM D 4169 schedule 1 testing, removed from the bottle, dedusted, and reweighed to determine percent loss for each bottle of tablets.
  • Table 19 contains tablet hardness testing information from this study. Average tablet hardness is illustrated in Figure 2. The tablet hardness determination from this study should only be used to determine hardness levels to the nearest whole number kp value, due to the fluctuation in tablet hardness values.
  • Table 20 contains oral disintegration times for tablets from this study. Average oral disintegration times are illustrated in Figure 3. The desired oral disintegration target of 30 - 90 seconds in the mouth was achieved for tablets with a hardness of 8.0 kp or less. The level of hardness of 10.0 kp provided tablets outside this range by 21 seconds.
  • Table 21 contains results of the friability test as a percent loss. Friability as average percent loss is illustrated in Figure 4. Hardness values of 6 kp and 8 kp yielded friability results above 1 %. A hardness value of 10 kp was required to reach a friability level of ⁇ 1 %.
  • Table 22 contains the results of the ship test from this study. Percent tablet loss as a function of tablet hardness is illustrated in Figure 5. There was a less than 1 % loss over the 6.0 kp and 10.0 kp tablet hardness during the ship test. The 8.0 kp tablet hardness resulted in an average 2.1 % loss.
  • Tablets manufactured with a hardness value of 6 and 8 kp with the formulation of Table 9 allows for both an average oral disintegration time of approximately 30 to 90 seconds and a friability that allows for multi-dose packaging (as well as single-dose packaging).
  • Tablet hardness testing has an associated percent error, which limits hardness determination to ⁇ 1 kp at best. The variability increases predictably as the hardness value increases.
  • the purpose of this example is to characterize process parameters and determine in-process tablet specification ranges for the nutritional supplement tablet.
  • Tablets utilized for this example were manufactured according to the process described above and exemplified in Figure 1 utilizing the raw materials listed in Table 23 to form the tablet detailed in Table 9. Specifically, the required non-active raw materials of Table 23 were dispensed into a 5 cubic ft. V blender. Only half of the LUDIFLASH® was initially mixed with the other five non-active raw materials (i.e., the KOLLIDON® CL-SF, stearic acid, fruit punch flavor, magnesium stearate, and sucralose). The non-active raw materials were blended for 5 minutes in a 5 ft 3 V blender using the intensifier bar.
  • the active ingredient components listed in Table 9 were then added to the non-active raw material mixture as a premix (Table 25) and further blended for 10 minutes utilizing the intensifier bar.
  • the remainder of the LUDIFLASH® was added to the mixture in the blender, and this final mixture was blended for 15 minutes utilizing the intensifier bar.
  • the final mixture was fed into a Manesty Express D3B rotary 16 station, single action tablet press and pressed into tablets having a weight of 1250 mg +/- 50 mg (equivalent to +/- 4%) and a hardness of 8 kp +/- 2 kp.
  • the tablets were approximately 0.63 inch (1.6 mm) round, off-white, uncoated tablets, with both upper and lower surfaces being plain. The tablets were dedusted.
  • the tablets were tested to determine the amount of time required for the tablet to disintegrate.
  • the tablet was held in the mouth of the test patient similar to a lozenge so that it could be dissolved by the patient's saliva and agitation in the mouth (e.g., by movement of the tongue) without mastication of the tablet.
  • Friability was calculated as percent loss for each level using a standard friability apparatus for 100 rotations over 4 minutes.
  • Table 24 contains oral disintegration times for tablets from this study.
  • the desired oral disintegration target of 30 - 90 seconds in the mouth was achieved for tablets, with an average time to dissolve being 65 seconds.
  • Table 25 contains the results of the friability test as a percent loss. Tablets produced according to this procedure had a percent loss of 1.35%.
  • the purpose of this example is to illustrate a procedure for the preparation of a large batch of the nutritional supplement tablets for sale and patient consumption.
  • Tablets utilized for this example were manufactured according to the process described above and exemplified in Figure 1 utilizing the raw materials listed in Table 26 to form the tablet detailed in Table 9.
  • the required non-active raw materials of Table 26 were dispensed into a 5 cubic ft.
  • PK V blender Powderson-Kelley, East Stroudsburg, PA. Specifically, the following raw materials were added to the 5 cubic ft.
  • V blender in the following order: 18.00 kg of LUDIFLASH®, 450 g of Crospovidone, NF - KOLLIDON® CL-SF, 1080 g of stearic acid NF, 900 g of fruit punch flavor, N-C natural and artificial, 450 g of magnesium stearate NF, and 320 g of sucralose NF.
  • the blender was activated, as was the intensifier bar, and the materials were blended for 5 minutes. 7.60 kg of the vitamin premix was added to the blender.
  • the blender was again activated, as was the intensifier bar, and the materials were blended for 10 minutes. 16.25 kg of LUDIFLASH® was added to the blender.
  • the blender was again activated, as was the intensifier bar, and the materials were blended for 30 minutes.
  • the final mixed blend was discharged from the blender and collected for compression.
  • the final product was loaded in the product hopper on a Manesty D3B Rotary Tablet Press (Manesty, Knowsley, Merseyside, UK) and pressed into tablets having a weight of 1250 mg +/- 38 mg (equivalent to +/- 3.04%) and a hardness of 8 kp +/- 2 kp.
  • the tablets were approximately 0.63 inch (1.6 mm) round, off-white, uncoated tablets, with both upper and lower surfaces debossed with "PBT.” The tablets were dedusted.
  • DRIs Dietary Reference Intakes: Recommended Intakes for Individuals, Elements. Food and Nutrition Board, Institute of Medicine, National Academys, 2004.
  • DRIs Dietary Reference Intakes: Tolerable Upper Intake Levels (UL), Elements. Food and Nutrition Board, Institute of Medicine, National Academys, 2004.
  • DRIs Dietary Reference Intakes: Recommended Intakes for Individuals, Vitamins. Food and Nutrition Board, Institute of Medicine, National Academys, 2004.
  • DRIs Dietary Reference Intakes
  • UL Upper Intake Levels
  • Vitamins Vitamins. Food and Nutrition Board, Institute of Medicine, National Academys, 2004.
  • Dietary Reference Intakes (DRIs): Estimated Average Requirements for Groups. Food and Nutrition Board, Institute of Medicine, National Academys, 2004.
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Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012029655A1 (ja) * 2010-08-30 2012-03-08 国立大学法人東北大学 血液透析痙攣抑制剤
WO2017065623A1 (en) * 2015-10-16 2017-04-20 Mendoza Wendell Stable composition of vitamin c and zinc tablet
CN108495621A (zh) * 2016-01-15 2018-09-04 诺维克斯科技私人有限公司 稳定适口的维生素c和锌含片组合物
US10806768B2 (en) * 2016-05-26 2020-10-20 Stephen N. Pitcher Composition for promoting metallothionein production
WO2018039297A1 (en) * 2016-08-26 2018-03-01 Dabdoub Atif Dietary macro/micronutritional supplement for patients undergoing kidney dialysis
SE542106C2 (en) * 2016-08-26 2020-02-25 Atif M Dabdoub Dietary macro/micronutritional supplement for patients undergoing kidney dialysis
TWI644670B (zh) * 2017-02-02 2018-12-21 新加坡商諾維斯科學私人有限公司 穩定且適口之口服咀嚼錠劑
WO2019165222A1 (en) * 2018-02-23 2019-08-29 Dabdoub Atif Dietary macro/micronutritional supplement and applications thereof
SG11202012913XA (en) * 2019-01-23 2021-01-28 Mizkan Holdings Co Ltd Dried powder of edible plant, food and beverage, and production method therefor

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998046215A1 (en) * 1997-04-16 1998-10-22 Cima Labs Inc. Rapidly dissolving robust dosage form
WO2001011991A1 (en) * 1999-08-13 2001-02-22 Warner Chilcott Laboratories Ireland Limited Orally dissolvable prenatal multi-vitamin
WO2001012163A1 (en) * 1999-08-13 2001-02-22 Warner Chilcott Laboratories Ireland Limited Dual iron-containing nutritional supplement
WO2001039601A1 (en) * 1999-12-01 2001-06-07 Drugtech Corporation Nutritional composition
US20020071864A1 (en) * 1999-03-25 2002-06-13 Yuhan Corporation Rapidly disintegrable tablet for oral administration
WO2002055061A2 (en) * 2001-01-11 2002-07-18 Particle And Coating Technologies, Inc. Method of producing porous tablets with improved dissolution properties
WO2007042153A1 (en) * 2005-10-11 2007-04-19 Bayer Consumer Care Ag Mixture of iron and copper salts masking mettalic taste
EP1977734A1 (de) * 2007-04-03 2008-10-08 Royal College of Surgeons in Ireland Verfahren zur Herstellung schnelllöslicher Tabletten

Family Cites Families (55)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2965541A (en) * 1959-06-22 1960-12-20 Upjohn Co 17alpha-acetoxyprogesterone compositions for oral use and methods of using same
US3558768A (en) * 1969-12-19 1971-01-26 Sterling Drug Inc Sustained release pharmaceutical compositions
US4432975A (en) * 1981-04-13 1984-02-21 Icn Pharmaceuticals, Inc. Process for introducing vitamin B-12 into the bloodstream
US5288497A (en) * 1985-05-01 1994-02-22 The University Of Utah Compositions of oral dissolvable medicaments
US5785989A (en) * 1985-05-01 1998-07-28 University Utah Research Foundation Compositions and methods of manufacturing of oral dissolvable medicaments
US5228498A (en) * 1990-05-31 1993-07-20 Kabushiki Kaisha Kobe Seiko Sho Continuous casting equipment and continuous casting method
US5817294A (en) * 1990-11-02 1998-10-06 Arnold; Michael J. Plaque adsorbent oral composition and method
US5464632C1 (en) * 1991-07-22 2001-02-20 Prographarm Lab Rapidly disintegratable multiparticular tablet
US5405617A (en) * 1991-11-07 1995-04-11 Mcneil-Ppc, Inc. Aliphatic or fatty acid esters as a solventless carrier for pharmaceuticals
DE69211157T2 (de) * 1991-12-20 1996-10-02 Pfizer Poröse geformte abgabevorrichtung und verfahren zur herstellung derselbe
JP3069458B2 (ja) * 1992-01-29 2000-07-24 武田薬品工業株式会社 口腔内崩壊型錠剤およびその製造法
DE69332801T2 (de) * 1992-11-30 2004-01-29 Kv Pharm Co Geschmacksmaskierte pharmazeutische substanzen
FR2710637B1 (fr) * 1993-09-28 1995-12-08 Roquette Freres Mannitol pulvérulent de friabilité modérée et son procédé de préparation.
US5576014A (en) * 1994-01-31 1996-11-19 Yamanouchi Pharmaceutical Co., Ltd Intrabuccally dissolving compressed moldings and production process thereof
JPH11505258A (ja) * 1995-05-17 1999-05-18 セダーシナイ メディカル センター 小腸における消化および吸収を改善させる脂肪酸を含む組成物
US5607697A (en) * 1995-06-07 1997-03-04 Cima Labs, Incorporated Taste masking microparticles for oral dosage forms
WO1997022336A1 (en) * 1995-12-21 1997-06-26 Smithkline Beecham Corporation Direct compression carbonyl iron tablet
EP0839526A3 (de) * 1996-10-31 1999-01-07 Takeda Chemical Industries, Ltd. Festes pharmazeutisches Präparat mit schneller Auflösungs- oder Disintegrationeigenschaften
US5976568A (en) * 1997-02-21 1999-11-02 Medical Doctors' Research Institute, Inc. Modular system of dietary supplement compositions for optimizing health benefits and methods
FR2766089B1 (fr) * 1997-07-21 2000-06-02 Prographarm Lab Comprime multiparticulaire perfectionne a delitement rapide
WO1999004758A1 (en) * 1997-07-25 1999-02-04 Elan Corporation Plc A process for the preparation of a granulate suitable to the preparation of rapidly disintegrable mouth-soluble tablets
US6465009B1 (en) * 1998-03-18 2002-10-15 Yamanouchi Pharmaceutical Co., Ltd. Water soluble polymer-based rapidly dissolving tablets and production processes thereof
US6365182B1 (en) * 1998-08-12 2002-04-02 Cima Labs Inc. Organoleptically pleasant in-mouth rapidly disintegrable potassium chloride tablet
US6368625B1 (en) * 1998-08-12 2002-04-09 Cima Labs Inc. Orally disintegrable tablet forming a viscous slurry
ATE462417T1 (de) * 1998-08-13 2010-04-15 Cima Labs Inc Microemulsionen als feste dosisformen zur oralen verabreichung
US6270790B1 (en) * 1998-08-18 2001-08-07 Mxneil-Ppc, Inc. Soft, convex shaped chewable tablets having reduced friability
US20040013613A1 (en) * 2001-05-18 2004-01-22 Jain Rajeev A Rapidly disintegrating solid oral dosage form
FR2785538B1 (fr) * 1998-11-06 2004-04-09 Prographarm Laboratoires Comprime a delitement rapide perfectionne
US6740341B1 (en) * 1998-11-25 2004-05-25 Cima Labs Inc. Taste masking rapid release coating system
AU765526B2 (en) * 1999-08-17 2003-09-18 Novartis Consumer Health S.A. Rapidly dissolving dosage form and process for making same
US6316029B1 (en) * 2000-05-18 2001-11-13 Flak Pharma International, Ltd. Rapidly disintegrating solid oral dosage form
AU2001279284A1 (en) * 2000-07-05 2002-01-14 Capricorn Pharma, Inc Rapid-melt semi-solid compositions, methods of making same and methods of using same
WO2003009834A1 (en) * 2000-08-17 2003-02-06 Battey Alyce S Oral delivery of pharmaceuticals via encapsulation
US6887493B2 (en) * 2000-10-25 2005-05-03 Adi Shefer Multi component controlled release system for oral care, food products, nutraceutical, and beverages
US6733781B2 (en) * 2000-12-06 2004-05-11 Wyeth Fast dissolving tablet
US6692771B2 (en) * 2001-02-23 2004-02-17 Cima Labs Inc. Emulsions as solid dosage forms for oral administration
ATE432692T1 (de) * 2001-03-06 2009-06-15 Kyowa Hakko Kirin Co Ltd Tabletten, die in der mundhöhle schnell zerfallen
US6872405B2 (en) * 2001-05-10 2005-03-29 Yamanouchi Pharmaceutical Co., Ltd. Quick-disintegrating tablet in buccal cavity and manufacturing method thereof
US20030035839A1 (en) * 2001-05-15 2003-02-20 Peirce Management, Llc Pharmaceutical composition for both intraoral and oral administration
US6509040B1 (en) * 2001-06-22 2003-01-21 R.P. Scherer Corporation Fast dispersing dosage forms essentially free of mammalian gelatin
FR2831820B1 (fr) * 2001-11-05 2004-08-20 Ethypharm Sa Comprime orodispersible presentant une grande homogeneite et son procede de preparation
US6863901B2 (en) * 2001-11-30 2005-03-08 Collegium Pharmaceutical, Inc. Pharmaceutical composition for compressed annular tablet with molded triturate tablet for both intraoral and oral administration
US7118765B2 (en) * 2001-12-17 2006-10-10 Spi Pharma, Inc. Co-processed carbohydrate system as a quick-dissolve matrix for solid dosage forms
KR20040098009A (ko) * 2002-03-06 2004-11-18 교와 핫꼬 고교 가부시끼가이샤 구강 내 속붕괴성 정제
US6941948B2 (en) * 2002-03-07 2005-09-13 Vectura Drug Delivery Medicament storage and delivery devices
MXPA05010636A (es) * 2003-04-04 2005-12-12 Pharmacia Corp Comprimidos de multiparticulas preparados por compresion de liberacion oral prolongada.
US7749533B2 (en) * 2003-05-07 2010-07-06 Akina, Inc. Highly plastic granules for making fast melting tablets
US7282217B1 (en) * 2003-08-29 2007-10-16 Kv Pharmaceutical Company Rapidly disintegrable tablets
IN234086B (de) * 2003-10-15 2009-05-29 Fuji Chem Ind Co Ltd
US20070196475A1 (en) * 2004-04-30 2007-08-23 Withiam Michael C Rapidly disintegrating low friability tablets comprising silica materials
JP2006076971A (ja) * 2004-09-13 2006-03-23 Basf Ag 口腔内崩壊錠
EP2098225B8 (de) * 2005-01-06 2011-06-22 Cima Labs Inc. Geschmacksunterdrückungssystem für nicht weichgemachte Arzneimittel
KR20080007449A (ko) * 2005-05-03 2008-01-21 이노젠, 인크. 영양 보충물의 경점막 전달을 위한 식용 필름
JP5209492B2 (ja) * 2005-12-21 2013-06-12 ビーエーエスエフ ソシエタス・ヨーロピア 速崩性錠剤製造のための医薬製剤
US20070196494A1 (en) * 2006-02-17 2007-08-23 Arnaud Grenier Low-friability, patient-friendly orally disintegrating formulations

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998046215A1 (en) * 1997-04-16 1998-10-22 Cima Labs Inc. Rapidly dissolving robust dosage form
US20020071864A1 (en) * 1999-03-25 2002-06-13 Yuhan Corporation Rapidly disintegrable tablet for oral administration
WO2001011991A1 (en) * 1999-08-13 2001-02-22 Warner Chilcott Laboratories Ireland Limited Orally dissolvable prenatal multi-vitamin
WO2001012163A1 (en) * 1999-08-13 2001-02-22 Warner Chilcott Laboratories Ireland Limited Dual iron-containing nutritional supplement
WO2001039601A1 (en) * 1999-12-01 2001-06-07 Drugtech Corporation Nutritional composition
WO2002055061A2 (en) * 2001-01-11 2002-07-18 Particle And Coating Technologies, Inc. Method of producing porous tablets with improved dissolution properties
WO2007042153A1 (en) * 2005-10-11 2007-04-19 Bayer Consumer Care Ag Mixture of iron and copper salts masking mettalic taste
EP1977734A1 (de) * 2007-04-03 2008-10-08 Royal College of Surgeons in Ireland Verfahren zur Herstellung schnelllöslicher Tabletten

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
AGHA-MOHAMMADI SIAMAK ET AL: "Potential impacts of nutritional deficiency of postbariatric patients on body contouring surgery", PLASTIC AND RECONSTRUCTIVE SURGERY : JOURNAL OF THE AMERICAN SOCIETY OF PLASTIC SURGEONS ; OFFICIAL ORGAN OF THE AMERICAN ASSOCIATION OF PLASTIC SURGEONS ; OFFICIAL ORGAN OF THE AMERICAN SOCIETY OF AESTHETIC PLASTIC SURGERY ; OFFICIAL ORGAN OF THE AM, vol. 122, no. 6, 1 December 2008 (2008-12-01), pages 1901-1914, XP008170414, ISSN: 1529-4242, DOI: 10.1097/PRS.0B013E31818D20D6 *
See also references of WO2010077878A1 *

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